X-ray contrast agents

ABSTRACT

THE INVENTION PROVIDES X-RAY CONTRAST AGENTS AND COMPOSITIONS CONTAINING THEM. THE NEW AGENTS OF THE INVENTION ARE COMPOUNDS OF THE FORMULA:   (2,4,6-TRI(I-),3-(AC-N(-R1)-),5-(HOOC-)PHENYL)-N(-AC)-X-   N(-AC)-(2,4,6-TRI(I-),5-(HOOC-)-1,3-PHENYLENE)-N(-AC)-R2   OR A SALT THEREOF WITH A PHYSIOLOGICALLY ACCEPTABLE ORGANIC OR INORGANIC BASE, WHEREIN R1 IS A HYDROGEN ATOM OR AN ALKYL GROUP CONTAINING UP TO THREE CARBON ATOMS WHICH MAY BE SUBSTITUTED BY ONE OR TWO HYDROXY GROUPS; R2 IS A HYDROGEN ATOM, AN ALKYL GROUP CONTAINING UP TO THREE CARBON ATOMS WHICH MAY BE SUBSTITUTED BY ONE OR TWO HYDROXY GROUPS, OR A GROUP OF THE FORMULA:   (2,4,6-TRI(I-),3-(AC-N(-R1)-),5-(HOOC-)PHENYL)-N(-AC)-X-   AC IS AN ACETYL OR PROPIONYL GROUP; AND X IS AN ALKYLENE GROUP CONTAINING FROM 3 TO 6 CARBON ATOMS.

nited States Patent US. Cl. 260-518 A 1 Claim ABSTRACT OF THE DISCLOSUREThe invention provides X-ray contrast agents and compositions containingthem. The new agents of the invention are compounds of the formula:

or a salt thereof with a physiologically acceptable organic or inorganicbase, wherein R is a hydrogen atom or an alkyl group containing up tothree carbon atoms which may be substituted by one or two hydroxygroups; R is a hydrogen atom, an alkyl group containing up to threecarbon atoms which may be substituted by one or two hydroxy groups, or agroup of the formula:

Ac Ac Ac is an acetyl or propionyl group; and X is an alkylene groupcontaining from 3 to 6 carbon atoms.

ice

According to the invention, therefore, there are provided as newcompounds, compounds of the formula:

I COOH 10 COOH (I) in which R is a hydrogen atom or an alkyl groupcontaining up to 3 carbon atoms, which alkyl group may be substituted byone or two hydroxy groups; R is a hydrogen atom, an alkyl groupcontaining up to three carbon atoms which may be substituted by one ortwo hydroxy groups, or a group of the formula:

Ac is an acetyl or propionyl group; and X is an alkylene groupcontaining from 3 to 6 carbon atoms; and salts thereof with a physicallyacceptable organic or inorganic base.

Examples of compounds of Formula I in which R is other than a group:

4O OOH and which show good radio-opaque activity are listed in Table 1.

TABLE 1.-COMPOUNDS OF FORMULA I Compound R R Ac X M.P 0

CH3 CHaCO CH2CH2CH2CH2 250-53 CH3 CHaCO CHzCHzCHzCHzCHz 237- CH3 CHsCOCH2CH2CH2CH2CH2CH2 241- H CHaCHzCO CHzCHzCHz 251- H CHaCO CH2CH2CH2CH225256 CH3 CHsCO CHzCHzCHzCHz 246-49 H CHsCO CHzCHzCHz 242-48 H CHsCOCHzCHzCHzCHn 240-46 H CHKCO CHzCHzCHzCHa 24044 H CHsCO CH2CH2CH2CH224044 CHzCHzOH CHaCO CH2CH2CH2 288-90 12 CHzCHzOH CH3 CHaCO CH2CH2CH2CH2247-49 invention, that certain diand tri-(triodobenzene) derivatives, ashereinafter defined may be used as radio-opaque or X-ray contrastagents.

Examples of compounds of Formula I, in which R is a group which may berepresented by Formula II below, and having good properties asradiopaque agents, are listed in Table 2.

1 1 1 R1 l X X It I Acyl .Aeyl Acyl Aeyl Acyl Acyl I \I I \I I \I OOHOOH COOH (II) TABLE 2 COMPOUNDS OF FORMULA n in which R is a hydrogenatom or an alkyl group con- C talmng up to three carbon atoms; w1th a3,5-d1am1no-2,4, fiz R1 Acyl X MR3 6-triiodo-benzoic acid derivative ofthe formula:

CH3 CHgCO CHaCHzCHzCHa 250-55 16 02H, 011,00 CHzCHzCHgCHz H 17 H oHaooCHzCH CHzCHz 255-57 1s omomorr ornoo ontonzonzom 0 /N- Y The compoundsof Formula I and functional derivatives I thereof in accordance with theinvention are useful as 0011 (v) contrast agents in X-ray diagnosis fromthe point of view of their solubility, very good compatibility and lowtoxicity. When water-soluble products are desired the free carboxylicacids may be used in the form of water-soluble, nontoxic salts withinorganic or organic basis.

Different compounds of Formula I may be used in different forms of X-raydiagnosis. Their rheological properties make them particularly valuablein various forms of angiography. Furthermore, their fast renal excretionmake them suitable as contrast agents for investigating the kidneys andthe urinary tract.

The contrast agents may be administered as solutions or dispersions inwater, using solvents and carriers known per se, and the inventionfurther provides a radio-opaque composition comprising a compound ofFormula I or salt thereof in association with a carrier or diluent.

A suitable form for the administration of the compounds of the inventionas X-ray contrast agents is as an aqueous solution of a salt thereof.Sodium, methylglucamine and diethanolamine salts have been used withexcellent results. The salt may be prepared by adding the dicarboxylicof Formula I to an aqueous solution of the base.

The new compounds of Formula I may be prepared by reacting a3,5-diamino-2,4,6-triiodo-benzoic acid derivative of the formula:

I I /X-Hal Y N\ Ac I I C O O R (111) Hal-X\ XHal A0 A0 O O R (IV) inwhich X and Ac have the meanings defined above, R is a readilyhydrolysable group (e.g. a methyl or benzyl group), Hal is a halogenatom (preferably a chlorine or bromine atom) and Y is an amino group ora group:

in which Ac and Y have the meanings defined above and R is a hydrogenatom or a readily hydrolysable group to yield a compound of the formula:

I I I Y N N Y Ac Ae I I I I O 0 R 00R (VI) (when reacting a compound ofFormula III with a compound of Formula V), or

Y N Y A0 A0 Ac A0 I I I I -I (VII) (when reacting a compound of FormulaIV with a compound of Formula V) and thereafter, if desired, acylatingthe free amino groups (if any), and alkylating or hydroxyalkylating theacylamino groups and hydrolysing off the group R and R The reactionbetween the compound of Formula III or Formula IV is suitably carriedout in the presence of a solvent and dimethylformamide is a preferredsolvent but other solvents such as acetone or methyl ethyl ketone mayalso be used. The reaction may be carried out in the presence of acondensing agent such as sodium hydride or sodium hydroxide and theprogress of the reaction may be followed by thin layer chromatography.Chromatography, either paper or thin layer chromatography is verysuitable for controlling the purity of the desired end products. Thecompounds of Formulae III and V are conveniently reacted together insubstantially equimolar proportions whilst the compounds of Formulae IVand V are suitably reacted in a mole ratio of about 1:2.

The compounds of Formula 111 used in the preparation of new compounds ofthe invention may be prepared by reacting a compound of the formula:

H Y N A0 I I 0 0 R (VIII) in which R, Ac and Y have the meanings definedabove, with a dihalo compound of the formula:

The compounds of Formula IV used in the preparation of the new compoundsof the invention may be prepared by reacting a compound of the formula:

with a dihalo compound of the formula:

In order that the invention may be well understood, the followingexamples are given by Way of illustration only. The compounds wereidentified by the method of preparation as well as by analysis andNMR-spectrography.

EXAMPLE 1 Preparation of the compound of Formula III in which R=methyl,Y=N-methyl acetamido,

64.2 g. (0.1 mol) of methyl N-methyl-3,S-diacetamido-2,4,6-triiodobenzoate, 5.0 g. (0.1 mol) of sodium hydride (50% emulsionoil) and 200 ml. of dimethylformamide are stirred at about 25 C. until aclear solution is obtained. 26.0 g. (0.12 mol) 1,4-dibromobutane isadded to the solution and the reaction mixture is stirred for one hourat 25 C. and then poured into water. The resulting precipitate iscollected, washed with water and dried. Yield 70 g. After treatment withethanol the compound melts at 159-163 C.

By using the corresponding ethyl and benzyl esters, these are obtainedin which R is ethyl (M.P. 122-126 C.) and benzyl (M.P. 183185 C.).

By reacting methyl N-methyl-3,5-diacetamido-2,4,6-triiodobenzoate with1,3-dibromopropane in an analogous manner methylN-(3'-bromopropyl)-N'-methyl-3,S-diacetamido- 2,4,6-triiodobenzoate(M.P. 168-170 C.) is obtained. The corresponding benzyl (M.P. 187190 C.)and ethyl (M.P. 107-117 C.) esters may be obtained in an analogousmanner.

By using 1,5-dibromopentane, esters of N-(5'-bromopentyl) Nmethyl-3,5-diacetamido-2,4,6-triiodobenzoic acid are obtained. Methylester M.P. 184-188 C., benzyl ester M.P. 120-128 C.

Methyl N-(4'-bromobutyl(-N'-ethyl-3,S-diacetamido-Z, 4,6-triiodobenzoate(M.P. 168-176 C.) and methyl 3-methylacetamido-S-(4'-bromobutyl)-propionamido-2, 4,6- triiodobenzoate(M.P. 133-137 C.) are prepared in an analogous manner.

EXAMPLE 2 Preparation of a compound of Formula 111, in which Y=-NH 59.0g. (0.1 mol) of methyl 3-acetamido-5-amino-2,4,6- triodobenzoate and26.0 g. (0.12 mol) of 1,4-dibromobutane are dissolved with stirring atroom temperature in 200 ml. of dimethylformamide. 50 ml. (0.1 mol) of 2N sodium hydroxide is added to the solution and the reaction mixture isstirred at 25 C. until the reaction is complete. The reaction mixture isthen poured into water and the resulting precipitate is collected andwashed with water. After treatment with ether the resulting methyl 6 3(N 4'-bromobutyl)-acetamido-5-amino-2,4,6-triiod0- benzoate melts at170-175 C.

In an analogous manner starting materials of Formula VIII as listed inTable 3 may be used.

TABLE 3 Starting material of Formula VIII TABLE 3 STARTING MATERIAL OFFORMULA VIII 62.8 g. (0.1 mol) of methyl3,5-diacetamido-2,4,6-triiodobenzoate, 10.0 g. (0.2 mol) sodium hydride(50% emulsion in oil) and 250 ml. of dimethylformamide are stirred atabout 25 C. until a clear solution is obtained. This solution is droppedinto a mixture of 51.4 g. (0.24 mol) of 1,4-dibromobutane and 250 ml. ofdimethylformamide at such a rate that the temperature of the mixture iskept at about 25 C. Stirring is maintained overnight at roomtemperature. Part of the solvent is then removed by distillation and theresidue is poured into water. The resulting crystals are collected,washed with water and dried. Yield 84 g. After treatment with ethanolthe resulting compound, methyl N,N di(4'-bromobutyl)-3,5-diacetamido-2,4,6-triiodobenzoate melts at -140" C.

8.0 g. of sodium hydroxide, dissolved in 16 ml. of Water, may be usedinstead of sodium hydride.

The corresponding ethyl (M.P. 185-190 C.) and benzyl (M.P. 120-125 C.)esters may be prepared in an analogous manner.

In an analogous manner the methyl (M.P. 122-125 C.) and benzyl (M.P.144l47 C.) N,N'-di(4-brom0butyl)-3,5-dipropionamido-2,4,6-triiodobenzoates are prepared.

By using 1,5-dibromopentane methyl N,N'-di(5'-bromopentyl)3,5-diacetamido-2,4,6-triiodo-benzoate (M.P. 180-190 C.) is obtained.

From 1,6- dibromohexane methylN,N'-di-(6'-bromohexyl)-3,5-diacetamido-2,4,6-triiodobenzoate (M.P. C.)is obtained.

Suitable starting materials of Formula IX are listed in Table 4.

TABLE 4.-STARTING MATERIALS OF Suitable dihalo compounds are1,3-dichloropropane, 1,3-dibromopropane, 1,4-dibromobutane,1,5-dibromopentane and 1,6-dibromohexane.

EXAMPLE 4 6.42 g. (0.01 mol) of methyl N-methyl-3,5-diacetamido-2,4,6-triiodobenzoate and 0.25 g. (0.01 mol) of sodium hydride arestirred in 25 ml. of dimethyl formamide until a clear solution isobtained. 7.75 g. (0.01 mol) of methyl N-(4-bromobutyl)-N-methyl 3,5diacetamido-2,4,6- triiodobenzoate is added to the clear solution withstirring. The stirring is continued overnight, and the reaction mixtureis poured into water. The separated precipitate is collected and washedwith water. The resulting methyl ester melts at 235240 C. Hydrolysisyields the corresponding free acid (compound No. 1, Table 1) having amelting point of 250-25 3 C.

Starting from methyl or benzyl 3-acetamido-5-amino-2,4,6-triiodobenzoate and methyl N-(4-bromobuty1)N'-methyl-3,5-diacetamido-2,4,6-triiodobenzoate it is possi- 7 ble toobtain the corresponding dimeric ester, which after acetylation withacetic anhydride and hydrolysis to remove the methyl or benzyl groupsgives compound No. 6 in Table 1.

If the acylation is carried out using propionic anhydride instead ofacetic anhydride a corresponding asymmetric dimeric compound, containingthree acetyl groups and one priopionyl group, is obtained. M.P. of thefree acid (compound No. 14) 240248 C.

Hydroxyalkylation of the compounds may readily be performed by reactionwith an epoxide or a haloalkanol. For instance the compound No. 7 inTable 1 reacts with 2-chloroethanol to give compound No. 11. Similarlycompound No. 6 may be reacted with 2-chloroethanol to give compound No.12.

2 moles of a monomeric compound of Formula VIII may be reacted with 1mol of dihalo compound, and in this case the free acids may be used.Thus, for instance, compound No. 1, Table 1, may be prepared from 2 molof N-methyl-3,5-diacetamido-2,4,6-triiodobenzoic acid and 1 mol of1,4-dibromobutane. The compound so obtained is identical with thecompound prepared as stated above.

Compound No. 7, Table 1 may be prepared by reacting 2 mol of3-acetamido-5-amino-2,4,6-triiodobenzoic acid with 1 mol1,3-dibromopropane and acetylation of the resulting dimeric acid withacetic anhydride.

Using propionic anhydride instead of acetic anhydride a correspondingsymmetrical dimeric compound, containing two acetyl groups and twopropionyl groups, is obtained. MP. of the free acid (compound No. 13)259- 262" C.

Compound No. 7 as listed below may also suitably be prepared from anexcess of 3,5-diacetamido-2,4,6- triiodobenzoic acid and1,3-dibromopropane.

EXAMPLE 25.7 g. (0.04 mol) of methylN-methyl-3,5-diacetamido-2,4,6-triiodobenzoate, 1.0 g. (0.04 mol) sodiumhydride and 75 ml. of dimethylformamide are stirred at 25 C. until aclear solution is obtained. To this solution 18.0 g. (0.02 mol) ofmethyl N,N-bis-(4'-bromobutyl)- 3,5 diacetamido 2,4,6 triiodobenzoate isadded with stirring, and the reaction mixture is stirred overnight atroom temperature. The solvent is removed by distillation and the residuetreated with Water and methyl ethyl ketone. The resulting compound meltsat 205-215 C. The corresponding free acid is obtained after hydrolysis.The free acid is listed as compound -No. 15 in Table 2.

A number of compounds according to the invention of Formula I have beentested regarding their usefulness as contrast agents in arteriographyand angio-cardiography as well as in intravenous urography. Thecompounds have been tested in animal experiments with regard totoxicity, compatibility, blood pressure effect and haemolyticproperties. Compounds having good properties in these respect are listedin Tables 1 and 2 above.

8 EXAMPLE 6 Preparation of a solution for injection containing 300 mg.iodine/ml.

51.608 g. of compound No. 1, Table 1, 0.610 g. of methylglucamine and0.020 g. of Na-Ca-EDTA are suspended in a mixture of 50 ml. of sterilewater and 0.9 ml. of 0.25 N ammonia. 10 N sodium hydroxide is added toadjust the pH 7.4 with stirring and stirring is continued until a clearsolution is obtained. The solution is then diluted to 100.0 ml. andfiltered on a sterilising filter.

Injection solutions, containing salts of other contrast agents of theinvention may be prepared in an analogous manner. It is, of course,possible to prepare solutions having iodine concentrations other than300 mg./ml. The amount of iodine-containing contrast agent to be used iseasily calculated. It is possible to prepare injection solutions,containing salts of other physiologically inert organic or inorganicbases, and it is also possible for a person skilled in the art toprepare solutions, containing salts of difierent inert bases as well asso-called balanced injection solutions.

We claim:

1. A compound selected from compounds of the formula:

R i i R2 N N\ /N N\ Ac Ac Ac Ac I I I -I O OH O O OH and salts thereofwith physiologically acceptable organic or inorganic bases, wherein R isa hydrogen atom or an alkyl group containing up to three carbon atomswhich may be substituted by a hydroxy group; R is a hydrogen atom, analkyl group containing up to three carbon atoms which may be substitutedby a hydroxy group, or a group of the formula:

Ac is an acetyl or propionyl group; and X is an alkylene groupcontaining from 3 to 6 carbon atoms.

References Cited Finar, I. L.: Organic Chemistry, vol. I (1963), pub. byRichard Clay & Co., Inc. England (QP251F6) p. 312 relied on.

LORRAINE A. WEINBERGER, Primary Examiner L. A. THAXTON, AssistantExaminer US. Cl. X.R.

